tbuckley/cabot-search huggingface dataset:
<i>Notes from the Field:</i> Aircraft Wastewater Surveillance for Early Detection of SARS-CoV-2 Variants — John F. Kennedy International Airport, New York City, August–September 2022
Authors: Robert C. Morfino, Stephen M. Bart, Andrew Franklin, Benjamin H. Rome, Andrew P. Rothstein, Thomas W. S. Aichele, Siyao Lisa Li, Aaron Bivins, Ezra T. Ernst, Cindy R. Friedman
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

As SARS-CoV-2 testing declines worldwide, surveillance of international travelers for SARS-CoV-2 enables detection of emerging variants and fills gaps in global genomic surveillance (1).Because SARS-CoV-2 can be detected in feces and urine of some infected persons (2), wastewater surveillance in airports and on aircraft has been proposed by the global public health community † as a low-cost mechanism to monitor SARS-CoV-2 variants entering the United States.Sampling wastewater directly from aircraft can be used to link SARS-CoV-2 lineage data with flight origin countries without active engagement of travelers (3).During August 1-September 9, 2022, the biotech company Ginkgo Bioworks, in collaboration with CDC, evaluated the feasibility of SARS-CoV-2 variant detection in aircraft wastewater from incoming international flights.Aircraft wastewater samples were collected from selected flights from the United Kingdom, Netherlands, and France arriving at John F. Kennedy International Airport in New York City.Wastewater (approximately 0.25 gal [1 L]) was collected from each plane during normal maintenance using a device that attaches to the lavatory service panel port and the lavatory service truck hose.After concentration with affinity-capture magnetic nanoparticles (4), wastewater samples were tested for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR).§ Samples with cycle thresholds <40 underwent whole genome sequencing using ARTIC (version 4.1; ARTIC Network) primers.¶ Multiple lineages within samples were identified using Freyja, a tool for deconvolution of complex samples.**Sequences meeting quality control criteria (e.g., >70% genome coverage) † † were assigned to sublineages using
<i>Notes from the Field:</i> Epidemiologic Characteristics of SARS-CoV-2 Recombinant Variant XBB.1.5 — New York City, November 1, 2022–January 4, 2023
Authors: Elizabeth Luoma, Rebecca Rohrer, Hilary Parton, Scott Hughes, Enoma Omoregie, Faten Taki, Jade C. Wang, Saymon Akther, Helly Amin, Carolyn Chang, Iris Cheng, Steve Di Lonardo, Meredith Eddy, Lauren Firestein, Wenhui Li, Michelle Su, Ellen H. Lee
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Bivalent booster vaccination data were
Effect of Predeparture Testing on Postarrival SARS-CoV-2–Positive Test Results Among International Travelers — CDC Traveler-Based Genomic Surveillance Program, Four U.S. Airports, March–September 2022
Authors: Stephen M. Bart, Teresa C. Smith, Sarah Anne J. Guagliardo, Allison Taylor Walker, Benjamin H. Rome, Siyao Lisa Li, Thomas W. S. Aichele, Rob Stein, Ezra T. Ernst, Robert C. Morfino, Martin S. Cetron, Cindy R. Friedman
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Beginning December 6, 2021, all international air passengers boarding flights to the United States were required to show either a negative result from a SARS-CoV-2 viral test taken ≤1 day before departure or proof of recovery from COVID-19 within the preceding 90 days (1). As of June 12, 2022, predeparture testing was no longer mandatory but remained recommended by CDC (2,3). Various modeling studies have estimated that predeparture testing the day before or the day of air travel reduces transmission or importation of SARS-CoV-2 by 31%-76% (4-7). Postarrival SARS-CoV-2 pooled testing data from CDC's Traveler-based Genomic Surveillance program were used to compare SARS-CoV-2 test results among volunteer travelers arriving at four U.S. airports during two 12-week periods: March 20-June 11, 2022, when predeparture testing was required, and June 12-September 3, 2022, when predeparture testing was not required. In a multivariable logistic regression model, pooled nasal swab specimens collected during March 20-June 11 were 52% less likely to be positive for SARS-CoV-2 than were those collected during June 12-September 3, after adjusting for COVID-19 incidence in the flight's country of origin, sample pool size, and collection airport (adjusted odds ratio [aOR] = 0.48, 95% CI = 0.39-0.58) (p<0.001). These findings support predeparture testing as a tool for reducing travel-associated SARS-CoV-2 transmission and provide important real-world evidence that can guide decisions for future outbreaks and pandemics.
AP-1–independent NFAT signaling maintains follicular T cell function in infection and autoimmunity
Authors: Abhinav Seth, Yoshiyuki Yokokura, Jin-Young Choi, Justin A. Shyer, Aurobind Vidyarthi, Joe Craft
Journal: The Journal of Experimental Medicine (2023)

Coordinated gene expression programs enable development and function of T cell subsets. Follicular helper T (Tfh) cells coordinate humoral immune responses by providing selective and instructive cues to germinal center B cells. Here, we show that AP-1-independent NFAT gene expression, a program associated with hyporesponsive T cell states like anergy or exhaustion, is also a distinguishing feature of Tfh cells. NFAT signaling in Tfh cells, maintained by NFAT2 autoamplification, is required for their survival. ICOS signaling upregulates Bcl6 and induces an AP-1-independent NFAT program in primary T cells. Using lupus-prone mice, we demonstrate that genetic disruption or pharmacologic inhibition of NFAT signaling specifically impacts Tfh cell maintenance and leads to amelioration of autoantibody production and renal injury. Our data provide important conceptual and therapeutic insights into the signaling mechanisms that regulate Tfh cell development and function.
NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling
Authors: Mikhail Tarasov, Heather L. Struckman, Yusuf Olgar, Alec Miller, Mustafa Demirtas, Vladimir Bogdanov, Radmila Terentyeva, Andrew M. Soltisz, Xiaolei Meng, Dennison Min, Galina Sakuta, Izabella Dunlap, Antonia D. Duran, Mark P. Foster, Jonathan P. Davis, Dmitry Terentyev, Sándor Györke, Rengasayee Veeraraghavan, Przemysław B. Radwański
Journal: Journal of Clinical Investigation (2023)

Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels. Here, we provide evidence implicating NaV dysregulation within transverse (T) tubules in D96V-CaM–associated arrhythmias. D96V-CaM induced a proarrhythmic late Na+ current (INa) by impairing inactivation of NaV1.6, but not the predominant cardiac NaV isoform NaV1.5. We investigated arrhythmia mechanisms using mice with cardiac-specific expression of D96V-CaM (cD96V). Super-resolution microscopy revealed close proximity of NaV1.6 and RyR2 within T-tubules. NaV1.6 density within these regions increased in cD96V relative to WT mice. Consistent with NaV1.6 dysregulation by D96V-CaM in these regions, we observed increased late NaV activity in T-tubules. The resulting late INa promoted aberrant Ca2+ release and prolonged APD in myocytes, leading to LQT and ventricular tachycardia in vivo. Cardiac-specific NaV1.6 KO protected cD96V mice from increased T-tubular late NaV activity and its arrhythmogenic consequences. In summary, we demonstrate that D96V-CaM promoted arrhythmias by dysregulating LTCCs and NaV1.6 within T-tubules and thereby facilitating aberrant Ca2+ release.
Association of Brain Metastases With Survival in Patients With Limited or Stable Extracranial Disease
Authors: Alyssa Y. Li, Karolina Gaebe, Amna Zulfiqar, Grace Lee, Katarzyna J. Jerzak, Arjun Sahgal, Steven Habbous, Anders W. Erickson, Sunit Das
Journal: JAMA Network Open (2023)

Intracranial metastatic disease (IMD) is a severe complication of cancer with profound prognostic implications. Patients with IMD in the setting of limited or stable extracranial disease (IMD-SE) may represent a unique and understudied subset of patients with IMD with superior prognosis.To evaluate overall survival (OS), progression-free survival (PFS), and intracranial PFS (iPFS) in patients with IMD-SE secondary to any primary cancer.Records were identified from MEDLINE, EMBASE, CENTRAL, and gray literature sources from inception to June 21, 2021.Studies in English reporting OS, PFS, or iPFS in patients with IMD-SE (defined as IMD and ≤2 extracranial metastatic sites) and no prior second-line chemotherapy or brain-directed therapy were selected.Author, year of publication, type of study, type of primary cancer, and outcome measures were extracted. Random-effects meta-analyses were performed to estimate effect sizes, and subgroup meta-analysis and metaregression were conducted to measure between-study differences in February 2022.The primary end point was OS described as hazard ratios (HRs) and medians for comparative and single-group studies, respectively. Secondary end points were PFS and iPFS.Overall, 68 studies (5325 patients) were included. IMD-SE was associated with longer OS (HR, 0.52; 95% CI, 0.39-0.70) and iPFS (HR, 0.63; 95% CI, 0.52-0.76) compared with IMD in the setting of progressive extracranial disease. The weighted median OS estimate for patients with IMD-SE was 17.9 months (95% CI, 16.4-22.0 months), and for patients with IMD-PE it was 8.0 months (95% CI, 7.2-12.8 months). Pooled median OS for all patients with IMD-SE was 20.9 months (95% CI, 16.35-25.98 months); for the subgroup with breast cancer it was 20.2 months (95% CI, 10.43-38.20 months), and for non-small cell lung cancer it was 27.5 months (95% CI, 18.27-49.66 months). Between-study heterogeneity for OS and iPFS were moderate (I2 = 56.5%) and low (I2 = 0%), respectively.In this systematic review and meta-analysis of patients with IMD-SE, limited systemic disease was associated with improved OS and iPFS. Future prospective trials should aim to collect granular information on the extent of extracranial disease to identify drivers of mortality and optimal treatment strategies in patients with brain metastases.
Linear association between radioactive iodine dose and second primary malignancy risk in thyroid cancer
Authors: Kyeong Jin Kim, Kyoung Jin Kim, Jimi Choi, Nam Hoon Kim, Sin Gon Kim
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background We aimed to investigate whether the risk of second primary malignancy (SPM) in patients with thyroid cancer (TC) receiving radioactive iodine (RAI) therapy rises in a cumulative, dose-dependent manner compared with those not undergoing RAI. Methods Using the Korean National Health Insurance Service National Health Information Database (2002-2019), we investigated hazard ratios of SPM associated with RAI in TC. SPM was defined as a second primary malignancy diagnosed at least 1 year after TC diagnosis. Results Of 217 777 patients with TC (177 385 women and 40 392 men; mean [SD] age, 47.2 [11.6] years), 100 448 (46.1%) received RAI therapy. The median (IQR) follow-up duration was 7.7 (5.5-10.3) years, and the median (IQR) cumulative RAI dose was 3.7 (1.9-5.6) GBq. From 2004 to 2019, SPM incidence rates were 7.30 and 6.56 per 1000 person-years in the RAI and non-RAI groups, respectively, with an unadjusted hazard ratio of 1.09 (95% confidence interval = 1.05 to 1.13); this rate remained at 1.08 (95% confidence interval = 1.04 to 1.13) after adjustment for multiple clinical confounding factors. Notably, SPM risk increased significantly, from 3.7 GBq with full adjustments, and a strong linear association between cumulative RAI dose and SPM was observed in the restricted cubic spline analysis. Regarding cancer subtypes, myeloid leukemia and salivary gland, trachea, lung and bronchus, uterus, and prostate cancers were the most significantly elevated risks in patients who underwent RAI therapy. Conclusions This study identified that SPM risk increased linearly in a dose-dependent manner in patients with TC undergoing RAI therapy compared with those not undergoing RAI therapy.
Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial
Authors: Ingo K. Mellinghoff, Min Lu, Patrick Y. Wen, Jennie W. Taylor, Elizabeth A. Maher, Isabel Arrillaga-Romany, Katherine B. Peters, Benjamin M. Ellingson, Marc K. Rosenblum, Saewon Chun, Kha Le, Ania Tassinari, Sung Choe, Youssef Toubouti, Steven Schoenfeld, Shuchi S. Pandya, Islam Hassan, Lori Steelman, Jennifer L. Clarke, Timothy F. Cloughesy
Journal: Nature Medicine (2023)

Abstract Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against m IDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of d -2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with m IDH1 -R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1–97.6) and 91.1% (95% CrI, 72.0–97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with m IDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.
Network expansion of genetic associations defines a pleiotropy map of human cell biology
Authors: Inigo Barrio-Hernandez, Jeremy Schwartzentruber, Anjali Shrivastava, Noemi del-Toro, Asier Gonzalez, Qian Zhang, Edward Mountjoy, Daniel Suveges, David Ochoa, Maya Ghoussaini, Glyn Bradley, Henning Hermjakob, Sandra Orchard, Ian Dunham, Carl A. Anderson, Pablo Porras, Pedro Beltrao
Journal: Nature Genetics (2023)

Interacting proteins tend to have similar functions, influencing the same organismal traits. Interaction networks can be used to expand the list of candidate trait-associated genes from genome-wide association studies. Here, we performed network-based expansion of trait-associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share an underlying genetic and biological process. We identified 73 pleiotropic gene modules linked to multiple traits, enriched in genes involved in processes such as protein ubiquitination and RNA processing. In contrast to gene deletion studies, pleiotropy as defined here captures specifically multicellular-related processes. We show examples of modules linked to human diseases enriched in genes with known pathogenic variants that can be used to map targets of approved drugs for repurposing. Finally, we illustrate the use of network expansion scores to study genes at inflammatory bowel disease genome-wide association study loci, and implicate inflammatory bowel disease-relevant genes with strong functional and genetic support.
When Compromised Professional Fulfillment Compromises Professionalism
Authors: Ashwini Nadkarni, Kayla Behbahani, John Fromson
Journal: JAMA (2023)

This Viewpoint highlights the increasing levels of burnout among physicians, discusses how burnout can erode professionalism, and suggests possible steps physicians and health care organizations might take to lessen burnout and maintain professionalism in the setting of burnout.
On the climate emergency and the health of our patients: comment on the article by Dellaripa et al
Authors: Toni Hospach, Alexandre Belot, Michael W. Beresford, Frank Dressler, Tilmann Kallinich, Prassad Oommen, Clare E. Pain, Klaus Tenbrock, Frank Weller, Johannes Roth, Kirsten Minden, Claas Hinze, Oliver Sander, Christian M. Hedrich
Journal: Arthritis & Rheumatology (2023)

Disclosure form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions
Authors: Pu-Ste Liu, Yi-Ting Chen, Xiaoyun Li, Pei-Chun Hsueh, Sheue-Fen Tzeng, Hsi Chen, Pei-Zhu Shi, Xin Xie, Sweta Parik, Mélanie Planque, Sarah-Maria Fendt, Ping-Chih Ho
Journal: Nature Immunology (2023)

Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD+/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.
In situ expansion and reprogramming of Kupffer cells elicit potent tumoricidal immunity against liver metastasis
Authors: Wei Liu, Xia Zhou, Qi Yao, Chen Chen, Qing Zhang, Keshuo Ding, Lu Li, Zhutian Zeng
Journal: Journal of Clinical Investigation (2023)

Liver metastasis represents one of the most frequent malignant diseases with no effective treatment. Functional reprogramming of Kupffer cells (KCs), the largest population of hepatic macrophages, holds promise for treating liver cancer, but remains seldom exploited. Taking advantage of the superior capacity of KCs to capture circulating bacteria, we report that a single administration of attenuated Escherichia coli producing clustered regularly interspersed short palindromic repeats CasΦ (CRISPR/CasΦ) machinery enables efficient editing of genes of interest in KCs. Using intravital microscopy, we observed a failure of tumor control by KCs at the late stage of liver metastasis due to KC loss preferentially in the tumor core and periphery, resulting in inaccessibility of these highly phagocytic macrophages to cancer cells. Simultaneous disruption of MafB and c-Maf expression using the aforementioned engineered bacteria could overcome KC dysfunction and elicit remarkable curative effects against several types of metastatic liver cancer in mice. Mechanistically, bacterial treatment induced massive proliferation and functional reprogramming of KCs. These cells infiltrated into the tumor, dismantled macrometastases by nibbling cancer cells, and skewed toward proinflammatory macrophages to unleash antitumor T cell responses. These findings provide an immunotherapy strategy that could be applicable for treating liver metastasis and highlight the therapeutic potential of targeting tissue-resident macrophages in cancer.
Association of Proton Pump Inhibitor Use With Risk of Acquiring Drug-Resistant Enterobacterales
Authors: Roel P. J. Willems, Martijn C. Schut, Anna M. Kaiser, Thomas H. Groot, Ameen Abu-Hanna, Jos W. R. Twisk, Karin van Dijk, Christina M. J. E. Vandenbroucke-Grauls
Journal: JAMA Network Open (2023)

Importance Proton-pump inhibitors (PPIs) have been associated with the risk of colonization with drug-resistant bacteria; however, possible confounding by lifestyle-associated factors and disease severity casts doubt on this association, and whether the risk is dose dependent is not known. Objectives To assess the association between PPI use and the risk of acquiring drug-resistant Enterobacterales and to examine interactions with possible microbiome-altering agents. Design, Setting, and Participants This nested case-control study involved 2239 hospitalized adult (aged ≥18 years) patients identified from the microbiology laboratory database of Amsterdam University Medical Centers between December 31, 2018, and January 6, 2021. Patients in the case group had newly detected extended-spectrum β-lactamase (ESBL)– or carbapenemase-producing Enterobacterales (identified by clinical specimens). Risk-set sampling was used to assign patients with negative results for ESBL- and carbapenemase-producing Enterobacterales to the control group, who were then matched on a 5:1 ratio with patients in the case group by age and culture date. A second validation case-control study included matched pairs (1:1 ratio; 94 in each group) of patients who were prospectively enrolled. Exposures Proton pump inhibitor use and clinical data at 30 days (primary exposure) and 90 days (secondary exposure) before the date of culture. Main Outcomes and Measures Adjusted incidence rate ratios (aIRRs) of ESBL- or carbapenemase-producing Enterobacterales acquisition by PPI dose and time risk windows (30 days for the primary outcome and 90 days for the secondary outcome) were estimated using conditional logistic regression models. Results Among 2239 hospitalized patients (51.1% male; mean [SD] age, 60.9 [16.7] years), 374 were in the case group (51.6% male; mean [SD] age, 61.1 [16.5] years) and 1865 were in the matched control group (51.0% male; mean [SD] age, 60.9 [16.7] years). The aIRR for PPI use overall was 1.48 (95% CI, 1.15-1.91) at 30 days. Sensitivity analyses and the analysis of the pair-matched study with prospectively enrolled patients (aIRR, 2.96, 95% CI, 1.14-7.74) yielded similar results; findings were consistent in subgroups and corroborated by a negative-control exposure analysis. No association with microbiome-disturbing agents was found; laxatives and antibiotics were independently associated with a more than 2-fold increase in the risk of acquisition (antibiotics: aIRR, 2.78 [95% CI, 2.14-3.59]; laxatives: aIRR, 2.26 [95% CI. 1.73-2.94]). Conclusions and Relevance In this study, after careful control for confounding and sensitivity analyses, PPI use was associated with increases in the risk of acquiring ESBL- or carbapenemase-producing Enterobacterales among adult hospitalized patients. These findings emphasize the need for judicious use of PPIs.